Interstitial cystitis (IC) comprises severe bladder pain and urinary frequency and urgency, has objective diagnostic findings, and its pathogenesis is unknown. We have shown that first-degree relatives of IC patients have a relative risk of > 16. That this familial aggregation is not solely an environmental effect is reflected by our further findings of significantly greater concordance among monozygotic than dizygotic twins and occurrence of IC in 2nd and 3rd degree relatives who presumably have not shared households. Hypothesizing that alleles for IC are inherited in these families, we will recruit multiplex families, i.e. those with greater than or equal too 2 first degree relatives who meet NIDDK criteria for IC, via a national recruitment campaign directed at urologists, employing the Internet, and collaborating with the Interstitial Cystitis Association. Pedigrees will be constructed with family members assigned to intermediate categories of IC. We will perform linkage analysis seeking loci of susceptibility to IC. We estimate that >900 probands will be evaluated. Reasonable assumptions of eligibility and volunteer rates suggest we will enroll >450 multiplex families with >2400 family members donating DNA. To date, a survey has already identified 101 potential probands; 143 unsolicited, additional potential probands have contacted us. Parametric, non-parametric, and conditional analyses will be performed with attention to subgroups to maximize homogeneity and to intermediate categories to avoid misclassification. The large number of participants will provide substantial power. We will finely map linkage regions and perform family-based linkage and association tests. In parallel we will help to discover additional multiplex families for extension/replication studies. These data on pedigrees and genotypes and stored DNA, from properly informed participants, will be a valuable resource. The identification of alleles of susceptibility to IC may reveal clues to pathogenesis, clinical therapy, preventive strategy, and possibly gene therapies.